Disturbances in hormone secretion have been frequently described in depressed patients. To date, there have been few attempts to develop models to explain these pathophysiological disturbances in neuroendocrine regulation. Hormone secretion is both pulsatile and periodic, with each neuroendocrine axis being tonically modulated, through trophic activation and negative feedback inhibition. The activity within any axis is, therefore, rhythmic and specific patterns of activation have been described in different axes. These biological rhythms are reproducible and imply synchronized interactions between the different components of a neuroendocrine axis, as well as between axes. This complex process is ultimately regulated by the interaction between a hormone and its specific target cell receptor. While it is the target cell responses which are ultimately measured, it is clear they tell little about subtle changes in synchronization and regulation at different levels within a neuroendocrine axis. This proposal focuses upon neuroendocrine regulation and the synchronization of biological rhythms in depressed patients. It is anticipated that, during a depressive illness, there is a disruption in the normal phasic relationships of these rhythms, which could result in the previously described disturbances in hormone secretion. With treatment and clinical recovery, it is expected that the relationships among these rhythms will change and approach that found in health control subjects. These studies will, therefore, include both healthy subjects and depressed patients. The latter will be studied before treatment and again after clinical recovery. It is proposed to study the hypothalamic-pituitary-adrenal axis in some detail and determine the phase relationships both within the axis, as well as with other well established rhythms like the rest-activity cycle and core body temperature. This will be accomplished by monitoring activity and sleep, as well as measuring core body temperature and the plasma concentrations of cortisol, ACTH, B-LPH/B-endorphin and melatonin over a 60-hour period. These data will allow direct comparison of the phase relationships between these rhythms, as well as within the hypothalamic-pituitary-adrenal axis. Internal synchronization within the axis will be explored further by establishing the sensitivity of the axis to CRF, arginine vasopressin and ACTH at discrete times during the day. Since the hormone disturbances described in depression appear to reverse with clinical recovery, these studies should provide important new information about the nature of the pathophysiological disturbances which have been previously described in the hypothalamic-pituitary-adrenal axis of some depressed patients.